Metabolomics describes the systematic and comprehensive measure of small molecule metabolites (<1000 Da) present in biofluids, cells, tissues and organisms. Given the close coupling between physiology and metabolism, metabolomics holds the power to deeply phenotype humans - integrating DNA sequence variation, mRNA species levels, protein levels, environmental exposures, diet, and commensal host micro- organisms - all within a single global measurement. Such metabolomics measures allows for understanding the basic pathogenesis of human disease, as well as diagnosing of early disease, characterization of disease sub-states, and predicting drug responsiveness. Given the integrative and dynamic nature of the human circulating metabolome, high-throughput approaches that allow for assessment of metabolomics on population level scales (>100 to 1000 samples) are paramount. Recently, developments in robotic liquid handling and solid-phase extraction systems, coupled with advanced mass spectrometry now enable the high-throughput interrogation of the metabolome across tens of thousands of individuals. This proposal is for a RapidFire mass spectrometry system, to be used for the high-throughput characterization of the human metabolome in healthy and disease states. This instrument will be employed for understanding the metabolic determinants of diseases such as diabetes, renal disease and atherosclerosis; the response to therapeutic agents, such as statins; and probing the metabolic regulation of commensal micro-organisms. Importantly, this RapidFire instrument will be used for the study of humans and human samples, which are not possible using currently available approaches. In addition, this instrument will be used to engage the scientific community in metabolomics and for training of graduate students and postdoctoral fellows in the emerging discipline of metabolomics.
|Garratt, Michael; Lagerborg, Kim A; Tsai, Yi-Miau et al. (2018) Male lifespan extension with 17-? estradiol is linked to a sex-specific metabolomic response modulated by gonadal hormones in mice. Aging Cell :e12786|
|Grankvist, Nina; Watrous, Jeramie D; Lagerborg, Kim A et al. (2018) Profiling the Metabolism of Human Cells by Deep 13C Labeling. Cell Chem Biol 25:1419-1427.e4|
|Basu Ball, Writoban; Baker, Charli D; Neff, John K et al. (2018) Ethanolamine ameliorates mitochondrial dysfunction in cardiolipin-deficient yeast cells. J Biol Chem 293:10870-10883|
|Li, Zhao; Martin, Marcy; Zhang, Jin et al. (2017) Krüppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility. Circulation 136:1315-1330|